U.S. patent application number 12/436276 was filed with the patent office on 2009-12-10 for terpolymers containing lactide and glycolide.
Invention is credited to Jie Hu, Lothar W. Kleiner, Florencia Lim, Michael Ngo, Yiwen Tang, Mikael Trollsas.
Application Number | 20090306120 12/436276 |
Document ID | / |
Family ID | 43298019 |
Filed Date | 2009-12-10 |
United States Patent
Application |
20090306120 |
Kind Code |
A1 |
Lim; Florencia ; et
al. |
December 10, 2009 |
TERPOLYMERS CONTAINING LACTIDE AND GLYCOLIDE
Abstract
The present invention provides an amorphous terpolymer for a
coating on an implantable device for controlling release of drug
and methods of making and using the same.
Inventors: |
Lim; Florencia; (Union City,
CA) ; Trollsas; Mikael; (San Jose, CA) ; Ngo;
Michael; (San Jose, CA) ; Hu; Jie; (Sunnyvale,
CA) ; Kleiner; Lothar W.; (Los Altos, CA) ;
Tang; Yiwen; (San Jose, CA) |
Correspondence
Address: |
SQUIRE, SANDERS & DEMPSEY LLP
1 MARITIME PLAZA, SUITE 300
SAN FRANCISCO
CA
94111
US
|
Family ID: |
43298019 |
Appl. No.: |
12/436276 |
Filed: |
May 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11877622 |
Oct 23, 2007 |
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12436276 |
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12124991 |
May 21, 2008 |
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11877622 |
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Current U.S.
Class: |
514/291 ;
514/449; 514/772.7; 528/354 |
Current CPC
Class: |
A61L 2300/602 20130101;
A61L 31/10 20130101; A61L 2300/416 20130101; C08L 67/04 20130101;
A61L 31/10 20130101; A61L 31/16 20130101 |
Class at
Publication: |
514/291 ;
528/354; 514/772.7; 514/449 |
International
Class: |
A61K 47/34 20060101
A61K047/34; C08G 63/08 20060101 C08G063/08; A61K 31/436 20060101
A61K031/436; A61K 31/337 20060101 A61K031/337; A61P 9/00 20060101
A61P009/00 |
Claims
1. An implantable article, comprising a terpolymer having a glass
transition temperature of about 37.degree. C. or below, which
terpolymer comprises units derived from a lactide, glycolide, and a
monomer providing a low glass transition temperature (T.sub.g),
wherein the monomer providing the low T.sub.g is capable of forming
a homopolymer having a T.sub.g of 20.degree. C. or below, and
wherein units from the monomer providing the low T.sub.g provides
for solubility of a hydrophobic drug in a article so as to achieve
permeation controlled release of the drug from the article.
2. The implantable article of claim 1, wherein the monomer
providing the low T.sub.g is caprolactone.
3. The implantable article of claim 2, wherein the monomer
providing the low T.sub.g has a ratio of about 15 mole % or higher
of the total monomers forming the terpolymer.
4. The implantable article of claim 2, wherein the monomer
providing the low T.sub.g has a ratio of about 25 mole % or higher
of the total monomers forming the terpolymer.
5. The implantable article of claim 2, wherein the monomer
providing the low T.sub.g has a ratio of about 50 mole % or higher
of the total monomers forming the terpolymer.
6. The implantable article of claim 1, wherein the lactide has a
ratio of from about 20 mole % to about 75 mole % of the total
monomers forming the terpolymer.
7. The implantable article of claim 1, wherein the glycolide has a
ratio of from about 10 mole % to about 30 mole % of the total
monomers forming the terpolymer.
8. The implantable article of claim 2, which is a coating on an
implantable device.
9. The implantable article of claim 8, wherein the implantable
device is a stent.
10. The implantable article of claim 2, which is a bioabsorbable
stent.
11. The implantable article of claim 1, further comprising one or
more bioactive agent.
12. The implantable article of claim 1, wherein the terpolymer has
a T.sub.g from about 25.degree. C. to about 37.degree. C.
13. The implantable article of claim 11, wherein the terpolymer has
a T.sub.g from about 25.degree. C. to about 37.degree. C.
14. The implantable article of claim 11, wherein the bioactive
agent is selected from paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone derivatives,
rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof.
15. The implantable article of claim 12, wherein the bioactive
agent is selected from paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone derivatives,
rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof.
16. The implantable article of claim 13, wherein the bioactive
agent is selected from paclitaxel, docetaxel, estradiol,
17-beta-estradiol, nitric oxide donors, super oxide dismutases,
super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone derivatives,
rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, and combinations
thereof.
17. A method of fabricating an implantable medical device,
comprising forming an article comprising a terpolymer having a
glass transition temperature of about 40.degree. C. or below, which
terpolymer comprises units derived from a lactide, glycolide, and a
monomer providing a low T.sub.g low glass transition temperature
(T.sub.g), wherein the monomer providing the low T.sub.g is capable
of forming a homopolymer having a T.sub.g of 20.degree. C. or
below, and wherein units from the monomer providing the low T.sub.g
provides for solubility of a hydrophobic drug in a article so as to
achieve permeation controlled release of the drug from the
article.
18. The method of claim 17, wherein the monomer providing the low
T.sub.g is caprolactone.
19. The method of claim 18, wherein the monomer providing the low
T.sub.g has a ratio of about 15 mole % or higher of the total
monomers forming the terpolymer.
20. The method of claim 18, wherein the monomer providing the low
T.sub.g has a ratio of about 25 mole % or higher of the total
monomers forming the terpolymer.
21. The method of claim 18, wherein the low monomer providing the
low T.sub.g has a ratio of about 50 mole % or higher of the total
monomers forming the terpolymer.
22. The method of claim 17, wherein the lactide has a ratio of from
about 20 mole % to about 75 mole % of the total monomers forming
the terpolymer.
23. The method of claim 17, wherein the glycolide has a ratio of
from about 10 mole % to about 30 mole % of the total monomers
forming the terpolymer.
24. The method of claim 18, which is a coating on an implantable
device.
25. The method of claim 24, wherein the implantable device is a
stent.
26. The method of claim 18, which is a bioabsorbable stent.
27. The method of claim 17, wherein the terpolymer has a T.sub.g
from about 25.degree. C. to about 37.degree. C.
28. The method of claim 18, wherein the terpolymer has a T.sub.g
from about 25.degree. C. to about 37.degree. C.
29. A method of treating, preventing, or ameliorating a vascular
medical condition, comprising implanting in a patient an
implantable article according to claim 1, wherein the vascular
medical condition is selected from restenosis, atherosclerosis,
thrombosis, hemorrhage, vascular dissection or perforation,
vascular aneurysm, vulnerable plaque, chronic total occlusion,
claudication, anastomotic proliferation (for vein and artificial
grafts), bile duct obstruction, urethral obstruction, tumor
obstruction, or combinations of these.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part application of U.S.
application Ser. No. 11/877,622, filed Oct. 23, 2007. This is also
a continuation-in-part application of U.S. application Ser. No.
12/124,991, filed on May 21, 2008. The teachings in these two prior
applications are incorporated herein in their entirety by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a bioabsorbable device
comprising amorphous polymers for controlling the release of a drug
from the device.
BACKGROUND OF THE INVENTION
[0003] Percutaneous coronary intervention (PCI) is a procedure for
treating heart disease. A catheter assembly having a balloon
portion is introduced percutaneously into the cardiovascular system
of a patient via the radial, brachial or femoral artery. The
catheter assembly is advanced through the coronary vasculature
until the balloon portion is positioned across the occlusive
lesion. Once in position across the lesion, the balloon is inflated
to a predetermined size to radially compress the atherosclerotic
plaque of the lesion to remodel the lumen wall. The balloon is then
deflated to a smaller profile to allow the catheter to be withdrawn
from the patient's vasculature.
[0004] Problems associated with the above procedure include
formation of intimal flaps or torn arterial linings which can
collapse and occlude the blood conduit after the balloon is
deflated. Moreover, thrombosis and restenosis of the artery may
develop over several months after the procedure, which may require
another angioplasty procedure or a surgical by-pass operation. To
reduce the partial or total occlusion of the artery by the collapse
of the arterial lining and to reduce the chance of thrombosis or
restenosis, a stent is implanted in the artery to keep the artery
open.
[0005] Drug delivery stents have reduced the incidence of in-stent
restenosis (ISR) after PCI (see, e.g., Serruys, P. W., et al., J.
Am. Coll. Cardiol. 39:393-399 (2002)), which has plagued
interventional cardiology for more than a decade. However, a few
challenges remain in the art of drug delivery stents. For example,
release of a drug from a coating formed of an amorphous may often
have a burst release of the drug, resulting in insufficient control
release of the drug.
[0006] Aliphatic polyesters are used in pharmaceutical and
biomedical applications, including for example surgical sutures and
drug delivery systems (Albertsson 2003; Greenwald 1994; Langer
2000; Nasongkla 2004). Poly(L-lactide) (PLLA) is one of the most
widely studied polymer biomaterials, attractive for its
biodegradable and biocompatible properties. However, PLLA is not
ideally suited for many aspects of drug delivery, including those
involving drug-eluting stents. This is due to the immiscibility of
most drugs with PLLA, including potent hydrophobic drugs for which
this immiscibility leads to burst release, or to shutdown of the
release.
[0007] Therefore, there is a need for a coating that provides for a
controlled release of a drug in the coating.
[0008] The embodiments of the present invention address the
above-identified needs and issues.
SUMMARY OF THE INVENTION
[0009] Provided herein is an implantable article comprising a
terpolymer having a glass transition temperature of about
37.degree. C. or below. The terpolymer comprises units derived from
a lactide, glycolide, and a monomer providing a low glass
transition temperature (T.sub.g). The article can be a coating on
an implantable device or a bioabsorbable implantable device such as
a bioabsorbable stent. In some embodiments, a requisite attribute
of the third monomer is that, if a homopolymer were to be formed of
the third monomer, the homopolymer would have a T.sub.g
sufficiently low (e.g., below about 20.degree. C.) such that the
terpolymer including the third monomer has a T.sub.g below
37.degree. C. In addition, a coating comprising a terpolymer
described herein provides for permeation controlled release of a
hydrophobic drug.
[0010] In some embodiments, the monomer providing the low T.sub.g
is caprolactone (CL). In some embodiments, the terpolymer can
contain sufficient content of polycaprolactone (PCL) to bring
T.sub.g down to about 25.degree. C. to about 30.degree. C. with
good miscibility with the drug.
[0011] In some embodiments, in the terpolymer, the monomer
providing the low T.sub.g (e.g., caprolactone) has a ratio of about
15 mole % or higher, about 25 mole % or higher, or about 50 mole %
or higher of the total monomers forming the terpolymer.
[0012] In some embodiments, in the terpolymer, the lactide has a
ratio of from about 20 mole % to about 75 mole % of the total
monomers forming the terpolymer.
[0013] In some embodiments, in the terpolymer, the glycolide has a
ratio of from about 10 mole % to about 30 mole % of the total
monomers forming the terpolymer.
[0014] In some embodiments, the implantable article and the various
embodiments above can further comprise one or more bioactive agent.
Examples of such bioactive agents can be paclitaxel, docetaxel,
estradiol, 17-beta-estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone acetate,
rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, or combinations
thereof.
[0015] In some embodiments, the coating can include one or more
other biocompatible polymers, which are described in more detail
below.
[0016] The present invention also provides a method of making and
using the implantable article and the various embodiments disclosed
above.
[0017] The implantable article described herein can be formed on an
implantable device such as a stent or formed as an implantable
device such as a bioabsorbable stent, which can be implanted in a
patient to treat, prevent, mitigate, or reduce a vascular medical
condition, or to provide a pro-healing effect. In some embodiments,
the vascular medical condition or vascular condition is a coronary
artery disease (CAD) and/or a peripheral vascular disease (PVD).
Some examples of such vascular medical diseases are restenosis
and/or atherosclerosis.
[0018] Some other examples of these conditions include thrombosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, urethral obstruction, tumor obstruction, or
combinations of these.
BRIEF DESCRIPTION OF DRAWINGS
[0019] FIG. 1 shows the relationship of one day or three day
cumulative everolimus drug release versus glass transition
temperature (T.sub.g) of polymers.
[0020] FIG. 2 shows 1 shows the relationship of one day or three
day cumulative everolimus drug release versus X value of
polymers.
[0021] FIG. 3 shows a) .sup.1H NMR and b) .sup.13C NMR spectra of
poly(L-lactide-co-.epsilon.-caprolactone-co-glycolide) terpolymer
(Table 5, entry 5).
[0022] FIG. 4 shows DSC thermogram (10.degree. C./min) of
terpolymer 5: (a) first heating run; (b) second heating run.
[0023] FIGS. 5a and 5b show SEM images of LA:CL:GA terpolymer
coated stents, using (a) terpolymer 2 (60:17:23) and (b) terpolymer
4 (77:17:6). Cracks in the coating of (b) are indicated by the
arrows.
[0024] FIG. 6 shows on-stent drug release profile of a terpolymer
coating with a LA:CL:GA composition of 68:18:14, and a molecular
weight of 61,000 g/mole (Table 5, entry 3), using drug-to-polymer
(d/p) ratios of 1/1, 1/2 and 1/3.
[0025] FIG. 7 shows drug release profile with a d/p=1/3 of
terpolymers with similar LA:CL:GA compositions and different
molecular weights (M.sub.w): 22000 g/mole (data represented by
sphere symbols) (Table 1, entry 1) and 41000 g/mole (data
represented by square symbols) (Table 5, entry 2).
DETAILED DESCRIPTION
[0026] Provided herein is an implantable article comprising a
terpolymer having a glass transition temperature of about
37.degree. C. or below. The terpolymer comprises units derived from
a lactide, glycolide, and a monomer providing a low glass
transition temperature (T.sub.g). The article can be a coating on
an implantable device or a bioabsorbable implantable device such as
a bioabsorbable stent. In some embodiments, a requisite attribute
of the third monomer is that, if a homopolymer were to be formed of
the third monomer, the homopolymer would have a T.sub.g
sufficiently low (e.g., below about 20.degree. C.) such that the
terpolymer including the third monomer has a T.sub.g below
37.degree. C. In addition, a coating comprising a terpolymer
described herein provides for permeation controlled release of a
hydrophobic drug.
[0027] In some embodiments, the monomer providing the low T.sub.g
is caprolactone (CL). In some embodiments, the terpolymer can
contain sufficient content of polycaprolactone (PCL) to bring
T.sub.g down to about 25.degree. C. to about 30.degree. C. with
good miscibility with the drug.
[0028] In some embodiments, in the terpolymer, the monomer
providing the low T.sub.g (e.g., caprolactone) has a ratio of about
15 mole % or higher, about 25 mole % or higher, or about 50 mole %
or higher of the total monomers forming the terpolymer.
[0029] In some embodiments, in the terpolymer, the lactide has a
ratio of from about 20 mole % to about 75 mole % of the total
monomers forming the terpolymer.
[0030] In some embodiments, in the terpolymer, the glycolide has a
ratio of from about 10 mole % to about 30 mole % of the total
monomers forming the terpolymer.
[0031] In some embodiments, the implantable article and the various
embodiments above can further comprise one or more bioactive agent.
Examples of such bioactive agents can be paclitaxel, docetaxel,
estradiol, 17-beta-estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutases mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
biolimus, tacrolimus, dexamethasone, dexamethasone acetate,
rapamycin, rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(ABT-578), zotarolimus, Biolimus A9 (Biosensors International,
Singapore), AP23572 (Ariad Pharmaceuticals), .gamma.-hiridun,
clobetasol, pimecrolimus, imatinib mesylate, midostaurin, feno
fibrate, prodrugs thereof, co-drugs thereof, or combinations
thereof.
[0032] In some embodiments, the coating can include one or more
other biocompatible polymers, which are described in more detail
below.
[0033] The present invention also provides a method of making and
using the implantable article and the various embodiments disclosed
above.
[0034] The implantable article described herein can be formed on an
implantable device such as a stent or formed as an implantable
device such as a bioabsorbable stent, which can be implanted in a
patient to treat, prevent, mitigate, or reduce a vascular medical
condition, or to provide a pro-healing effect. In some embodiments,
the vascular medical condition or vascular condition is a coronary
artery disease (CAD) and/or a peripheral vascular disease (PVD).
Some examples of such vascular medical diseases are restenosis
and/or atherosclerosis.
[0035] Some other examples of these conditions include thrombosis,
hemorrhage, vascular dissection or perforation, vascular aneurysm,
vulnerable plaque, chronic total occlusion, claudication,
anastomotic proliferation (for vein and artificial grafts), bile
duct obstruction, urethral obstruction, tumor obstruction, or
combinations of these.
[0036] An article formed of the terpolymer described herein can
substantially or completely degrade or absorb within about 24
months, within about 18 months, within about 12 months, within
about 9 months, within about 6 months, within about 4 months,
within about 3 months, within about 2 months, or within about 1
month after implantation of a medical device comprising the
coating. In some embodiments, the coating can completely degrade or
fully absorb within 24 months after implantation of a medical
device comprising the coating.
[0037] As used herein, the term "substantially degrade or absorb"
shall mean about 80 mole % or higher (e.g., about 90 mole % or
higher; or about 95 mole % or higher) degradation or absorption of
the coating within the specified period. The term "fully degrade or
absorb" shall mean about 99 mole % or higher (e.g., 100 mole %)
degradation or absorption of the coating within the specified
period.
Definitions
[0038] Wherever applicable, the definitions to some terms used
throughout the description of the present invention as provided
below shall apply.
[0039] The terms "biologically degradable" (or "biodegradable"),
"biologically erodable" (or "bioerodable"), "biologically
absorbable" (or "bioabsorbable"), and "biologically resorbable" (or
"bioresorbable"), in reference to polymers and coatings, are used
interchangeably and refer to polymers and coatings that are capable
of being completely or substantially completely degraded,
dissolved, and/or eroded over time when exposed to physiological
conditions and can be gradually resorbed, absorbed and/or
eliminated by the body, or that can be degraded into fragments that
can pass through the kidney membrane of an animal (e.g., a human),
e.g., fragments having a molecular weight of about 40,000 Daltons
(40 K Daltons) or less. The process of breaking down and eventual
absorption and elimination of the polymer or coating can be caused
by, e.g., hydrolysis, metabolic processes, oxidation, enzymatic
processes, bulk or surface erosion, and the like. Conversely, a
"biostable" polymer or coating refers to a polymer or coating that
is not biodegradable.
[0040] Whenever the reference is made to "biologically degradable,"
"biologically erodable," "biologically absorbable," and
"biologically resorbable" stent coatings or polymers forming such
stent coatings, it is understood that after the process of
degradation, erosion, absorption, and/or resorption has been
completed or substantially completed, no coating or substantially
little coating will remain on the stent. Whenever the terms
"degradable," "biodegradable," or "biologically degradable" are
used in this application, they are intended to broadly include
biologically degradable, biologically erodable, biologically
absorbable, and biologically resorbable polymers or coatings.
[0041] "Physiological conditions" refer to conditions to which an
implant is exposed within the body of an animal (e.g., a human).
Physiological conditions include, but are not limited to, "normal"
body temperature for that species of animal (approximately
37.degree. C. for a human) and an aqueous environment of
physiologic ionic strength, pH and enzymes. In some cases, the body
temperature of a particular animal may be above or below what would
be considered "normal" body temperature for that species of animal.
For example, the body temperature of a human may be above or below
approximately 37.degree. C. in certain cases. The scope of the
present invention encompasses such cases where the physiological
conditions (e.g., body temperature) of an animal are not considered
"normal."
[0042] In the context of a blood-contacting implantable device, a
"prohealing" drug or agent refers to a drug or agent that has the
property that it promotes or enhances re-endothelialization of
arterial lumen to promote healing of the vascular tissue.
[0043] As used herein, a "co-drug" is a drug that is administered
concurrently or sequentially with another drug to achieve a
particular pharmacological effect. The effect may be general or
specific. The co-drug may exert an effect different from that of
the other drug, or it may promote, enhance or potentiate the effect
of the other drug.
[0044] As used herein, the term "prodrug" refers to an agent
rendered less active by a chemical or biological moiety, which
metabolizes into or undergoes in vivo hydrolysis to form a drug or
an active ingredient thereof. The term "prodrug" can be used
interchangeably with terms such as "proagent", "latentiated drugs",
"bioreversible derivatives", and "congeners". N. J. Harper, Drug
latentiation, Prog Drug Res., 4: 221-294 (1962); E. B. Roche,
Design of Biopharmaceutical Properties through Prodrugs and
Analogs, Washington, D.C.: American Pharmaceutical Association
(1977); A. A. Sinkula and S. H. Yalkowsky, Rationale for design of
biologically reversible drug derivatives: prodrugs, J. Pharm. Sci.,
64:181-210 (1975). Use of the term "prodrug" usually implies a
covalent link between a drug and a chemical moiety, though some
authors also use it to characterize some forms of salts of the
active drug molecule. Although there is no strict universal
definition of a prodrug itself, and the definition may vary from
author to author, prodrugs can generally be defined as
pharmacologically less active chemical derivatives that can be
converted in vivo, enzymatically or nonenzymatically, to the
active, or more active, drug molecules that exert a therapeutic,
prophylactic or diagnostic effect. Sinkula and Yalkowsky, above; V.
J. Stella et al., Prodrugs: Do they have advantages in clinical
practice?, Drugs, 29: 455-473 (1985).
[0045] The terms "polymer" and "polymeric" refer to compounds that
are the product of a polymerization reaction. These terms are
inclusive of homopolymers (i.e., polymers obtained by polymerizing
one type of monomer by either chain or condensation polymers),
copolymers (i.e., polymers obtained by polymerizing two or more
different types of monomers by either chain or condensation
polymers), condensation polymers (polymers made from condensation
polymerization, terpolymers, etc., including random (by either
chain or condensation polymers), alternating (by either chain or
condensation polymers), block (by either chain or condensation
polymers), graft, dendritic, crosslinked and any other variations
thereof.
[0046] As used herein, the term "implantable" refers to the
attribute of being implantable in a mamrnal (e.g., a human being or
patient) that meets the mechanical, physical, chemical, biological,
and pharmacological requirements of a device provided by laws and
regulations of a governmental agency (e.g., the U.S. FDA) such that
the device is safe and effective for use as indicated by the
device. As used herein, an "implantable device" may be any suitable
substrate that can be implanted in a human or non-human animal.
Examples of implantable devices include, but are not limited to,
self-expandable stents, balloon-expandable stents, coronary stents,
peripheral stents, stent-grafts, catheters, other expandable
tubular devices for various bodily lumen or orifices, grafts,
vascular grafts, arterio-venous grafts, by-pass grafts, pacemakers
and defibrillators, leads and electrodes for the preceding,
artificial heart valves, anastomotic clips, arterial closure
devices, patent foramen ovale closure devices, cerebrospinal fluid
shunts, and particles (e.g., drug- eluting particles,
microparticles and nanoparticles). The stents may be intended for
any vessel in the body, including neurological, carotid, vein
graft, coronary, aortic, renal, iliac, femoral, popliteal
vasculature, and urethral passages. An implantable device can be
designed for the localized delivery of a therapeutic agent. A
medicated implantable device may be constructed in part, e.g., by
coating the device with a coating material containing a therapeutic
agent. The body of the device may also contain a therapeutic
agent.
[0047] An implantable device can be fabricated with a coating
containing partially or completely a biodegradable/bioabsorbable/
bioerodable polymer, a biostable polymer, or a combination thereof.
An implantable device itself can also be fabricated partially or
completely from a biodegradable/bioabsorbable/ bioerodable polymer,
a biostable polymer, or a combination thereof.
[0048] As used herein, a material that is described as a layer or a
film (e.g., a coating) "disposed over" an indicated substrate
(e.g., an implantable device) refers to, e.g., a coating of the
material deposited directly or indirectly over at least a portion
of the surface of the substrate. Direct depositing means that the
coating is applied directly to the exposed surface of the
substrate. Indirect depositing means that the coating is applied to
an intervening layer that has been deposited directly or indirectly
over the substrate. In some embodiments, the term a "layer" or a
"film" excludes a film or a layer formed on a non-implantable
device.
[0049] In the context of a stent, "delivery" refers to introducing
and transporting the stent through a bodily lumen to a region, such
as a lesion, in a vessel that requires treatment. "Deployment"
corresponds to the expanding of the stent within the lumen at the
treatment region. Delivery and deployment of a stent are
accomplished by positioning the stent about one end of a catheter,
inserting the end of the catheter through the skin into a bodily
lumen, advancing the catheter in the bodily lumen to a desired
treatment location, expanding the stent at the treatment location,
and removing the catheter from the lumen.
[0050] As used herein, the term "amorphous" refers to having a
crystallinity less than 50 mole % in a terpolymer. In some
embodiments, the term "amorphous" can refer to having a
crystallinity less than about 40 mole %, less than about 30 mole %,
less than about 20 mole %, less than about 10 mole %, less than
about 5 mole %, less than about 1%, less than about 0.5 mole %, or
less than about 0.1% in a terpolymer.
Permeation CFontrolled Release of Drug
[0051] Permeation controlled release of a hydrophobic drug is
important in providing a controlled release of the hydrophobic
drug. In the terpolymer described herein, units from the third
monomer, in addition to lowering T.sub.g of the terpolymer, assist
in solubilizing a hydrophobic drug in a coating comprising the
terpolymer. This helps control release of the hydrophobic drug. For
example, where a coating formed of the terpolymer includes a
hydrophobic drug such as everolimus, the polymer is not hydrophobic
enough to solubilize everolimus, and hence, upon deployment of a
medical device comprising such a coating, release of the drug from
the coating would be either a burst release if concentration of
drug is above percolation or a shut-down after a short surface
burst if concentration is below percolation. Percolation will be
close to 30 to 35 mole % drug.
[0052] In contrast, via solubility of a hydrophobic drug (drug in
polymer), release of the drug from the coating would be permeation
controlled release which can be well controlled and reproducible.
Without solubility of the drug in polymer, a coating including the
polymer and drug would have phase separation, and to provide
release of drug from the coating, one would need to have a
concentration of drug above percolation. In addition, release of
drug from such a coating would be burst release, which is
controlled by connecting drug channels or pores in the coating
(channel or pore release), which control is difficult to
achieve.
[0053] In some embodiments, the term "permeation" can be used
interexchangeably with the term "diffusion."
Polymer Composition
[0054] The terpolymer described herein can have different contents
of the lactide (A), glycolide (B), and a third, low T.sub.g monomer
(C). The terpolymer can be expressed in this general formula
A.sub.xB.sub.yC.sub.z, wherein x, y and z are ratios of A, B, and
C, respectively. Within the terpolymer, monomers A, B, and C can
have any sequence of arrangement, for example, ABC, BAC, CBA,ACB,
ABAC, ABBC, BABC, BAAC, BACC, CBCA, CBBA, CBAA, ABACA, ABACB,
ABACC, BABCA, BABCB, BABCC, etc. As outlined in some embodiments, a
sequence of monomers or units can have more than one units of a
monomer, which are described in more detail below.
[0055] Terpolymers with different contents of these three monomers
have different properties with regard to, e.g., rate of
degradation, mechanical properties, drug permeability, water
permeability, and drug release rate, depending on a particular
composition of the monomers in the terpolymer.
[0056] In some embodiments, the terpolymer can have a T.sub.g below
about 37.degree. C. This terpolymer can have units derived from
D-lactide, L-lactide, or D,L-lactide from about 10 mole % to about
80 mole %. Monomers such as D-lactide, L-lactide, glycolide, and
dioxanone can crystallalize if present in high concentration in a
polymer. However, crystallization of units from any of these
monomers can be minimized or prevented if concentration of each is
below 80 mole % in the polymer. Therefore, the composition of a
terpolyrner described herein shall include units of D-lactide or
L-lactide at about 10-80 mole %, units of glycolide at about 5-80
mole % and units from the third, low T.sub.g monomer at about 5-60
mole %. The terpolymer can have a weight-average molecular weight
(M.sub.w) of about 10K Daltons or above, preferrably from about 20K
Daltons to about 600K Daltons.
[0057] Ratios of units from the lactide, glycolide and the monomer
providing the low T.sub.gS can vary, forming a terpolymer having
different properties, e.g., different degradation rates, different
rates of release of a drug from a coating formed of the terpolymer,
different drug permeability, different flexibility or mechanical
properties. As noted above, generally, the glycolide provides an
accelerated or enhanced degradation of the terpolymer, the lactide
monomer provides mechanical strength to the terpolymer, and the
third, low T.sub.g monomer can enhance drug permeability, water
permeability, and enhancing degradation rate of the polymer,
imparting greater flexibility and elongation, and improving
mechanical properties of a coating formed of the terpolymer.
[0058] In some embodiments, the ratio of the various monomers can
vary along the chain of the terpolymer. In such a terpolymer, one
point of the chain of polymer can be heavy with one monomer while
another point of the chain can be light with the same monomer, for
example. If a monofunctional initiator is used, and if the selected
monomers have highly different reactivity ratios, then a gradient
of composition is generated as the monomers are consumed during the
polymerization. In another methodology, such a terpolymer can be
prepared by so-called gradient polymerization wherein during the
polymerization a first or second monomer is progressively added to
the reactor containing all, or a portion of, the first monomer.
(Matyjaszewski K. and Davis T. P. eds. Handbook of Radical
Polymerization, John Wiley & Sons, 2002, p. 789). Yet a third
method is by introducing blocks of various ratios of the monomers
into the chain of the terpolymer.
[0059] In some embodiments, the terpolymer described herein can be
used to build one or more blocks in combination with other blocks
such as poly(ethylene glycol) (PEG) or other blocks of
biodegradable or biodurable polymers described below.
[0060] Randomness of the terpolymer described herein can be
measured by randomness index. Generally, a perfectly alternating
co-polymer would have a degree of randomness of 1. Conversely, in
some embodiments, the terpolymer can include all the repeating
units of the monomers in three blocks, the lactide block, the
glycolide block, and the block of the third, low T.sub.g monomer.
Such a terpolymer would have a degree of randomness of 0. These are
known as block copolymers. In some other embodiments, the
terpolymer can have a degree of randomness ranging from above 0 to
below 1, for example, about 0.01, about 0.02, about 0.05, about
0.1, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about
0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7,
about 0.75, about 0.8, about 0.85, about 0.9, about 0.95, or about
0.99. Generally, for a crystalline domain to develop, one usually
needs a pentad (i.e. the same 5 repeat units or monomers in
sequence). Therefore, in some embodiments, one factor to control
the randomness of the terpolymer is to keep the repeat units or
monomers in sequence in the terpolymer below 5, e.g., 1, 2, 3, or
4.
[0061] Randomness in a polymer can be readily determined by
established techniques in the art. One such technique is NMR
analysis ((see, e.g., J. Kasperczyk, Polymer, 37(2):201-203 (1996);
Mangkom Srisa-ard, et al., Polym Int., 50:891-896 (2001)).
[0062] Randomness of an amorphous terpolymer can be readily
controlled or varied using techniques known in the art. For
example, randomness in a batch reactor is controlled by
polymerization temperature and type of solvent where the monomer
reactivity ratios will change. For continuous reactors, it will
also depend on monomer feed ratios and temperature. Secondarily,
there is also a pressure effect on reactivity ratios. Monomers
relative reactivity is also important, so you can control it by
selecting monomers with similar or different reactivity.
[0063] As mentioned previously, in some embodiments, one requisite
attribute of the third monomer is that, if a homopolymer were to be
formed of the third monomer, the homopolymer would have a T.sub.g
below about -20.degree. C. The third monomer can be any monomer
that is capable of forming a terpolymer with lactide and glycolide.
In some embodiments, the third low T.sub.g monomer is a lactone, a
carbonate, a thiocarbonate, an oxaketocycloalkane, or a
thiooxaketocyclolakane. In some embodiments, the lactone,
carbonate, thiocarbonate, oxaketocycloalkane, or
thiooxaketocyclolakane can have hydrocarbyl or alkoxy
substituent(s). In some embodiments, the substituent(s) can include
hetero atom(s) such as a halo (F, Cl, Br or I) group(s). Some
examples of substituents include, but are not limited to, methoxy,
ethoxy, or a C1-C12 hydrocarbon group.
[0064] Some examples of the third monomer are given below in Table
1.
TABLE-US-00001 TABLE 1 Examples of low T.sub.g monomers
##STR00001## ##STR00002## ##STR00003## ##STR00004## 1. tri- 2.
substituted 3. tri- 4. 1,3,5-trioxa-4- methylene trimethylele
carbonate methylene ketocyclohexane carbonate R.sub.1-R.sub.6 are
dithio- T.sub.g = -15.degree. C. independently H, carbonate
CH.sub.3O, C.sub.1-C.sub.12 hydrocarbon ##STR00005## ##STR00006##
##STR00007## ##STR00008## 5. tri- 6. 1-thio-3,5-dioxa-2- 7.
1-thio-3,5- 8. .xi.-enantholactone methylene ketocyclohexane
dioxa-4- thio- keto- carbonate cyclohexane ##STR00009##
##STR00010## ##STR00011## ##STR00012## 9. tetra- 10. pentamethylene
11. .beta.-butyro- 12. substituted .beta.- methylene carbonate
lactone butyrolactone carbonate R1-R4 are independently H,
CH.sub.3O, C.sub.1-C.sub.12 hydrocarbon ##STR00013## ##STR00014##
##STR00015## ##STR00016## 13. di- 14. 1,3-dioxa-cyclo 15. 1,4- 16.
1,4-dioxa-2-keto oxanone hexyl-6-one dioxa-7-keto cycloheptane or
cycloheptane 1,4-dioxa- or 1,4-dioxa- cycloheptyl-2-one
cycloheptyl- 7-one
[0065] In some embodiments, monomers such as meso-lactide or
thiolactones can be used to form a terpolymer with the third
monomer. In these embodiments, the meso-lactide or thiolactones can
be used with lactide or can replace lactide to form a terpolymer
with the third, low T.sub.g monomer.
[0066] Note, ratios of monomers can also affect the overall T.sub.g
of the terpolymer and the drug release rate (RR). This is clearly
seen in Table 2 below and FIGS. 1 and 2.
TABLE-US-00002 TABLE 2 MW T.sub.g Tm RR RR P (LA-GA-CL) (kDa)
(.degree. C.) (.degree. C.) (D:P).sup.a 1-day 30-day X.sup.b
20/30/50 154 -17.2 -- 1:3 99.9 99.9 10.60 35/15/50 131 -16.7 -- 1:3
99.9 99.9 10.18 40/30/30** 149 6 -- 40/30/30 88.0 .+-. 4.0 97.4
.+-. 1.5 10.62 45/30/25 136 12.8 -- 1:3 83 99.9 10.63 50/25/25**
156 14 -- 1:3 58.6 .+-. 3.0 82.3 .+-. 2.3 10.49* 60/15/25 101 13.0
-- 1:3 66.7 94.5 10.20* 60/15/25 140 18 -- 1:3 47.4 .+-. 1.3 67.4
.+-. 4.5 10.20* 75/10/15 161 32 -- 1:3 8.9 .+-. 3.5 13.2 .+-. 4.7
10.06 70/20/10 155 40 -- 1:3 13.2 .+-. 1.3 10.6 .+-. 8.0 10.36
85/7.5/7.5 168 42 148.5 1:3 16.3 .+-. 2.4 17.8 .+-. 3.4 9.95*
75/25/0 136 54 -- 1:2 68.7 .+-. 1.04 69.1 .+-. 1.9 10.51 75/25/0
136 54 -- 1:3 68.7 .+-. 1.04 69.1 .+-. 1.9 10.51 75/25/0* 139 54.6
-- 1:3 58.0 75.1 10.51* 82/18/0* 193 59.5 141.1 1:3 11.7 10.6 10.37
.sup.adrug to polymer ratio. .sup.bX values are described in
Hubbell et al., J. Biomedical Materials Research, 24:1397-1411
(1990).
[0067] An embodiment of the invention polymer described above
includes caprolactone as the third monomer, which polymer is poly
poly(lactide-co-glycolide-co-caprolactone) (PLGACL). The features
and characteristics described in any of the preceding sections or
paragraphs pertaining to the terpolymer are all applicable to this
PLGACL polymer. Exemplary compositions and properties of this
PLGACL terpolymer are described in Tables 3-4 and the Examples
described below.
Synthesis
[0068] In addition to the method of preparation polymers mentioned
above, in general, preparation of the terpolymer described herein
can be readily accomplished by established methods of polymer
synthesis. For example, a chosen composition of lactide, glycolide,
and the third monomer with any of the various ratios described
above can be subject to ring opening polymerization (ROP) to form a
terpolymer. Polymer synthesis by ROP is a well-documented method of
polymer synthesis and can be readily carried out by a person of
ordinary skill in the art. Some other methods of polymer synthesis
include, e.g., acid catalyzed polycondensation with removal of
water. This would start with the monomers in hydroxyl-acid form, or
as the cylic ester precursors. During the polymerization the water
formed would be distilled off. Alternatively, room temperature
polycondensations of the monomers in hydroxyl-acid form could be
performed by using Mitsunobo conditions (DEAD/TPP) or by using
dicyclohexylcarbodiimide with dimethylaminopyridine (DMAP) salt.
Examples of synthesis of the invention polymer is described
below.
TABLE-US-00003 TABLE 3 L-Lactide (LA), .epsilon.-Caprolactone (CL),
and Glycolide (GA) polymers (75-20-5 batches) Actual DSC
composition GPC 1.sup.st heat 2.sup.nd heat by .sup.1H M.sub.w
M.sub.n T.sub.m T.sub.m Polymer NMR (g/mol) (g/mol) PDI T.sub.g
(.degree. C.) (.degree. C.) T.sub.g (.degree. C.) (.degree. C.)
XZ/PLA-CL- 78:18:4 130,000 49,600 2.61 39 120 37 -- GA-75-20-5
batch #1 TR/PLA-CL- 77:17:6 22,800 12,500 1.83 21 (10-35) 75, 99,
35 GA-75-20-5- 110 (60-121) (22-43) batch#2 TR/PLA-CL- 68:25:7
26,600 16,500 1.61 18 69, 88, 17 -- GA-70-25-5- 107 (50-120)
batch#3 TR/PLA-CL- 79:16:5 89,400 40,500 2.21 19 (10-35) 75, 121 40
(27-46) -- GA-75-20-5-batch (60-133) #4 DC/PLA-CL- 78:17:6 137,000
68,000 2.01 144 (113-154) 49 (42-55) 146 GA-75-20-5-batch (130-153)
#5 (Sn:monomer = 1:4500) DC/PLA-CL- 77:19:4 99,000 57,000 1.73 28
(24-37) 112, 123 36 (14-42) -- GA-75-20-5-batch (91-133) #6
(Sn:monomer = 1:1100) DC/PLA-CL- 83:12:5 69,000 43,000 1.62 117,
130 43 (32-49) -- GA-75-20-5- (93-118) batch #7 (Sn:monomer =
1:4500) DC/PLA-CL- 79:17:3 52,000 34,000 1.54 27 (22-34) 103, 110
30 (17-38) -- GA-75-20-5-batch (86-119) #8 (Sn:monomer = 1:550)
DC/PLA-CL- 84:10:6 58,000 37,000 1.56 20 (16-24) 117, 122 45
(36-50) -- GA-75-20-5-batch (90-131) #9 (Zr:monomer = 1:4500)
DC/PLA-CL- 76:20:3 60,000 37,000 1.63 10-39 85, 102 36 (21-39) --
GA-75-20-5-batch (69-114) #10 (Zr:monomer = 1:1100)
TABLE-US-00004 TABLE 4 L-Lactide (LA), .epsilon.-Caprolactone (CL),
and Glycolide (GA) polymers (65-20-15 batches) DSC Actual GPC
1.sup.st heat 2.sup.nd heat composition M.sub.w M.sub.n T.sub.m
T.sub.m Polymer by .sup.1H NMR (g/mol) (g/mol) PDI T.sub.g
(.degree. C.) (.degree. C.) T.sub.g (.degree. C.) (.degree. C.)
TR/PLA-CL- 61:21:18 22,000 13,400 1.63 23 (1-33) -- 26 (13-35) --
GA-65-20-15- batch#1 TR/PLA-CL- 60:17:23 41,000 24,600 1.67 27
(17-41) 94, 103 30 (10-38) -- GA-65-20-15- (80-112) batch#2
TR/PLA-CL- 68:18:14 100, 700 60,900 1.65 32 (15-41) 75, 126 32
(16-45) -- GA-65-20-15- (55-145) batch #3 TR/PLA-CL- 69:8:23 79,500
44,700 1.78 16 (6-33) 44, 75, 127 35 (23-41) -- GA-65-20-15-
(33-155) batch #5 TR/PLA-CL- 58:26:16 69,300 41,000 1.69 16 (4-37)
75, 117 28 (15-34) -- GA-65-20-15- (69-160) batch #6 TR/PLA-CL-
69:17:14 77,500 45,200 1.71 29 (11-38) 79, 110 37 (18-43)
GA-65-20-15- (46-135) batch #7 TR/PLA-CL- 70:12:18 84,000 54,100
1.55 -- 52, 73 45 (32-49) GA-65-20-15- (42-81) batch #8
Biologically Active Agents
[0069] In some embodiments, the implantable device described herein
can optionally include at least one biologically active
("bioactive") agent. The at least one bioactive agent can include
any substance capable of exerting a therapeutic, prophylactic or
diagnostic effect for a patient.
[0070] Examples of suitable bioactive agents include, but are not
limited to, synthetic inorganic and organic compounds, proteins and
peptides, polysaccharides and other sugars, lipids, and DNA and RNA
nucleic acid sequences having therapeutic, prophylactic or
diagnostic activities. Nucleic acid sequences include genes,
antisense molecules that bind to complementary DNA to inhibit
transcription, and ribozymes. Some other examples of other
bioactive agents include antibodies, receptor ligands, enzymes,
adhesion peptides, blood clotting factors, inhibitors or clot
dissolving agents such as streptokinase and tissue plasminogen
activator, antigens for immunization, hormones and growth factors,
oligonucleotides such as antisense oligonucleotides and ribozymes
and retroviral vectors for use in gene therapy. The bioactive
agents could be designed, e.g., to inhibit the activity of vascular
smooth muscle cells. They could be directed at inhibiting abnormal
or inappropriate migration and/or proliferation of smooth muscle
cells to inhibit restenosis.
[0071] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
can include at least one biologically active agent selected from
antiproliferative, antineoplastic, antimitotic, anti-inflammatory,
antiplatelet, anticoagulant, antifibrin, antithrombin, antibiotic,
antiallergic and antioxidant substances.
[0072] An antiproliferative agent can be a natural proteineous
agent such as a cytotoxin or a synthetic molecule. Examples of
antiproliferative substances include, but are not limited to,
actinomycin D or derivatives and analogs thereof (manufactured by
Sigma-Aldrich, or COSMEGEN available from Merck) (synonyms of
actinomycin D include dactinomycin, actinomycin IV, actinomycin
I.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1); all taxoids
such as taxols, docetaxel, and paclitaxel and derivatives thereof;
all olimus drugs such as macrolide antibiotics, rapamycin,
everolimus, structural derivatives and functional analogues of
rapamycin, structural derivatives and functional analogues of
everolimus, FKBP-12 mediated mTOR inhibitors, biolimus,
perfenidone, prodrugs thereof, co-drugs thereof, and combinations
thereof. Examples of rapamycin derivatives include, but are not
limited to, 40-O-(2-hydroxy)ethyl-rapamycin (trade name everolimus
from Novartis), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus, manufactured by Abbott Labs.), Biolimus A9
(Biosensors International, Singapore), AP23572 (Ariad
Pharmaceuticals), prodrugs thereof, co-drugs thereof, and
combinations thereof.
[0073] An anti-inflammatory drug can be a steroidal
anti-inflammatory drug, a nonsteroidal anti-inflammatory drug
(NSAID), or a combination thereof. Examples of anti-inflammatory
drugs include, but are not limited to, alclofenac, alclometasone
dipropionate, algestone acetonide, alpha amylase, amcinafal,
amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra,
anirolac, anitrazafen, apazone, balsalazide disodium, bendazac,
benoxaprofen, benzydamine hydrochloride, bromelains, broperamole,
budesonide, carprofen, cicloprofen, cintazone, cliprofen,
clobetasol, clobetasol propionate, clobetasone butyrate, clopirac,
cloticasone propionate, cormethasone acetate, cortodoxone,
deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone
acetate, dexamethasone dipropionate, diclofenac potassium,
diclofenac sodium, diflorasone diacetate, diflumidone sodium,
diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
meglumine, fluocortin butyl, fluorometholone acetate, fluquazone,
flurbiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone,
methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,
naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,
orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,
pentosan polysulfate sodium, phenbutazone sodium glycerate,
pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine,
pirprofen, prednazate, prifelone, prodolic acid, proquazone,
proxazole, proxazole citrate, rimexolone, romazarit, salcolex,
salnacedin, salsalate, sanguinarium chloride, seclazone,
sermetacin, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol
pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate,
zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid),
salicylic acid, corticosteroids, glucocorticoids, tacrolimus,
pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations
thereof.
[0074] Alternatively, the anti-inflammatory agent can be a
biological inhibitor of pro- inflammatory signaling molecules.
Anti-inflammatory biological agents include antibodies to such
biological inflammatory signaling molecules.
[0075] In addition, the bioactive agents can be other than
antiproliferative or anti-inflammatory agents. The bioactive agents
can be any agent that is a therapeutic, prophylactic or diagnostic
agent. In some embodiments, such agents can be used in combination
with antiproliferative or anti-inflammatory agents. These bioactive
agents can also have antiproliferative and/or anti-inflammmatory
properties or can have other properties such as antineoplastic,
antimitotic, cystostatic, antiplatelet, anticoagulant, antifibrin,
antithrombin, antibiotic, antiallergic, and/or antioxidant
properties.
[0076] Examples of antineoplastics and/or antimitotics include, but
are not limited to, paclitaxel (e.g., TAXOL.RTM. available from
Bristol-Myers Squibb), docetaxel (e.g., Taxotere.RTM. from
Aventis), methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin.RTM. from
Pfizer), and mitomycin (e.g., Mutamycin(g from Bristol-Myers
Squibb).
[0077] Examples of antiplatelet, anticoagulant, antifibrin, and
antithrombin agents that can also have cytostatic or
antiproliferative properties include, but are not limited to,
sodium heparin, low molecular weight heparins, heparinoids,
hirudin, argatroban, forskolin, vapiprost, prostacyclin and
prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone
(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIa
platelet membrane receptor antagonist antibody, recombinant
hirudin, thrombin inhibitors such as ANGIOMAX (from Biogen),
calcium channel blockers (e.g., nifedipine), colchicine, fibroblast
growth factor (FGF) antagonists, fish oil (e.g., omega 3-fatty
acid), histamine antagonists, lovastatin (a cholesterol-lowering
drug that inhibits HMG-CoA reductase, brand name Mevacor.RTM. from
Merck), monoclonal antibodies (e.g., those specific for
platelet-derived growth factor (PDGF) receptors), nitroprusside,
phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,
serotonin blockers, steroids, thioprotease inhibitors,
triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric
oxide donors, super oxide dismutases, super oxide dismutase
mimetics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
estradiol, anticancer agents, dietary supplements such as various
vitamins, and a combination thereof.
[0078] Examples of cytostatic substances include, but are not
limited to, angiopeptin, angiotensin converting enzyme inhibitors
such as captopril (e.g., Capoten.RTM. and Capozide.RTM. from
Bristol-Myers Squibb), cilazapril and lisinopril (e.g.,
Prinivil.RTM. and Prinzide.RTM. from Merck).
[0079] Examples of antiallergic agents include, but are not limited
to, permirolast potassium. Examples of antioxidant substances
include, but are not limited to,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO). Other
bioactive agents include anti-infectives such as antiviral agents;
analgesics and analgesic combinations; anorexics; antihelmintics;
antiarthritics, antiasthmatic agents; anticonvulsants;
antidepressants; antidiuretic agents; antidiarrheals;
antihistamines; antimigrain preparations; antinauseants;
antiparkinsonism drugs; antipruritics; antipsychotics;
antipyretics; antispasmodics; anticholinergics; sympathomimetics;
xanthine derivatives; cardiovascular preparations including calcium
channel blockers and beta-blockers such as pindolol and
antiarrhythmics; antihypertensives; diuretics; vasodilators
including general coronary vasodilators; peripheral and cerebral
vasodilators; central nervous system stimulants; cough and cold
preparations, including decongestants; hypnotics;
immunosuppressives; muscle relaxants; parasympatholytics;
psychostimulants; sedatives; tranquilizers; naturally derived or
genetically engineered lipoproteins; and restenoic reducing
agents.
[0080] Other biologically active agents that can be used include
alpha-interferon, genetically engineered epithelial cells,
tacrolimus and dexamethasone.
[0081] A "prohealing" drug or agent, in the context of a
blood-contacting implantable device, refers to a drug or agent that
has the property that it promotes or enhances re-endothelialization
of arterial lumen to promote healing of the vascular tissue. The
portion(s) of an implantable device (e.g., a stent) containing a
prohealing drug or agent can attract, bind, and eventually become
encapsulated by endothelial cells (e.g., endothelial progenitor
cells). The attraction, binding, and encapsulation of the cells
will reduce or prevent the formation of emboli or thrombi due to
the loss of the mechanical properties that could occur if the stent
was insufficiently encapsulated. The enhanced re-endothelialization
can promote the endothelialization at a rate faster than the loss
of mechanical properties of the stent.
[0082] The prohealing drug or agent can be dispersed in the body of
the bioabsorbable polymer substrate or scaffolding. The prohealing
drug or agent can also be dispersed within a bioabsorbable polymer
coating over a surface of an implantable device (e.g., a
stent).
[0083] "Endothelial progenitor cells" refer to primitive cells made
in the bone marrow that can enter the bloodstream and go to areas
of blood vessel injury to help repair the damage. Endothelial
progenitor cells circulate in adult human peripheral blood and are
mobilized from bone marrow by cytokines, growth factors, and
ischemic conditions. Vascular injury is repaired by both
angiogenesis and vasculogenesis mechanisms. Circulating endothelial
progenitor cells contribute to repair of injured blood vessels
mainly via a vasculogenesis mechanism.
[0084] In some embodiments, the prohealing drug or agent can be an
endothelial cell (EDC)-binding agent. In certain embodiments, the
EDC-binding agent can be a protein, peptide or antibody, which can
be, e.g., one of collagen type 1, a 23 peptide fragment known as
single chain Fv fragment (scFv A5), a junction membrane protein
vascular endothelial (VE)-cadherin, and combinations thereof.
Collagen type 1, when bound to osteopontin, has been shown to
promote adhesion of endothelial cells and modulate their viability
by the down regulation of apoptotic pathways. S. M. Martin, et al.,
J. Biomed. Mater. Res., 70A: 10-19 (2004). Endothelial cells can be
selectively targeted (for the targeted delivery of immunoliposomes)
using scFv A5. T. Volkel, et al., Biochimica et Biophysica Acta,
1663:158-166 (2004). Junction membrane protein vascular endothelial
(VE)-cadherin has been shown to bind to endothelial cells and down
regulate apoptosis of the endothelial cells. R. Spagnuolo, et al.,
Blood, 103:3005-3012 (2004).
[0085] In a particular embodiment, the EDC-binding agent can be the
active fragment of osteopontin,
(Asp-Val-Asp-Val-Pro-Asp-Gly-Asp-Ser-Leu-Ala-Try-Gly). Other
EDC-binding agents include, but are not limited to, EPC (epithelial
cell) antibodies, RGD peptide sequences, RGD mimetics, and
combinations thereof.
[0086] In further embodiments, the prohealing drug or agent can be
a substance or agent that attracts and binds endothelial progenitor
cells. Representative substances or agents that attract and bind
endothelial progenitor cells include antibodies such as CD-34,
CD-133 and vegf type 2 receptor. An agent that attracts and binds
endothelial progenitor cells can include a polymer having nitric
oxide donor groups.
[0087] The foregoing biologically active agents are listed by way
of example and are not meant to be limiting. Other biologically
active agents that are currently available or that may be developed
in the future are equally applicable.
[0088] In a more specific embodiment, optionally in combination
with one or more other embodiments described herein, the
implantable device of the invention comprises at least one
biologically active agent selected from paclitaxel, docetaxel,
estradiol, nitric oxide donors, super oxide dismutases, super oxide
dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
tacrolimus, dexamethasone, dexamethasone acetate, rapamycin,
rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), Biolimus A9 (Biosensors International, Singapore),
AP23572 (Ariad Pharmaceuticals), pimecrolimus, imatinib mesylate,
midostaurin, clobetasol, progenitor cell-capturing antibodies,
prohealing drugs, prodrugs thereof, co-drugs thereof, and a
combination thereof. In a particular embodiment, the bioactive
agent is everolimus. In another specific embodiment, the bioactive
agent is clobetasol.
[0089] An alternative class of drugs would be
p-para-.alpha.-agonists for increased lipid transportation,
examples include feno fibrate.
[0090] In some embodiments, optionally in combination with one or
more other embodiments described herein, the at least one
biologically active agent specifically cannot be one or more of any
of the bioactive drugs or agents described herein.
Coating Construct
[0091] According to some embodiments of the invention, optionally
in combination with one or more other embodiments described herein,
a coating disposed over an implantable device (e.g., a stent) can
include an amorphous terpolymer described herein in a layer
according to any design of a coating. The coating can be a
multi-layer structure that includes at least one reservoir layer,
which is layer (2) described below, and can include any of the
following (1), (3), (4) and (5) layers or combination thereof:
[0092] a primer layer; (optional)
[0093] a reservoir layer (also referred to "matrix layer" or "drug
matrix"), which can be a drug-polymer layer including at least one
polymer (drug-polymer layer) or, alternatively, a polymer-free drug
layer;
[0094] a release control layer (also referred to as a
"rate-limiting layer") (optional);
[0095] a topcoat layer; and/or (optional);
[0096] a finishing coat layer. (optional).
[0097] In some embodiments, a coating of the invention can include
two or more reservoir layers described above, each of which can
include a bioactive agent described herein.
[0098] Each layer of a stent coating can be disposed over the
implantable device (e.g., a stent) by dissolving the amorphous
polymer, optionally with one or more other polymers, in a solvent,
or a mixture of solvents, and disposing the resulting coating
solution over the stent by spraying or immersing the stent in the
solution. After the solution has been disposed over the stent, the
coating is dried by allowing the solvent to evaporate. The process
of drying can be accelerated if the drying is conducted at an
elevated temperature. The complete stent coating can be optionally
annealed at a temperature between about 40.degree. C. and about
150.degree. C., e.g., 80.degree. C., for a period of time between
about 5 minutes and about 60 minutes, if desired, to allow for
crystallization of the polymer coating, and/or to improve the
thermodynamic stability of the coating.
[0099] To incorporate a bioactive agent (e.g., a drug) into the
reservoir layer, the drug can be combined with the polymer solution
that is disposed over the implantable device as described above.
Alternatively, if it is desirable a polymer-free reservoir can be
made. To fabricate a polymer-free reservoir, the drug can be
dissolved in a suitable solvent or mixture of solvents, and the
resulting drug solution can be disposed over the implantable device
(e.g., stent) by spraying or immersing the stent in the
drug-containing solution.
[0100] Instead of introducing a drug via a solution, the drug can
be introduced as a colloid system, such as a suspension in an
appropriate solvent phase. To make the suspension, the drug can be
dispersed in the solvent phase using conventional techniques used
in colloid chemistry. Depending on a variety of factors, e.g., the
nature of the drug, those having ordinary skill in the art can
select the solvent to form the solvent phase of the suspension, as
well as the quantity of the drug to be dispersed in the solvent
phase. Optionally, a surfactant can be added to stabilize the
suspension. The suspension can be mixed with a polymer solution and
the mixture can be disposed over the stent as described above.
Alternatively, the drug suspension can be disposed over the stent
without being mixed with the polymer solution.
[0101] The drug-polymer layer can be applied directly or indirectly
over at least a portion of the stent surface to serve as a
reservoir for at least one bioactive agent (e.g., drug) that is
incorporated into the reservoir layer. The optional primer layer
can be applied between the stent and the reservoir to improve the
adhesion of the drug-polymer layer to the stent. The optional
topcoat layer can be applied over at least a portion of the
reservoir layer and serves as a rate-limiting membrane that helps
to control the rate of release of the drug. In one embodiment, the
topcoat layer can be essentially free from any bioactive agents or
drugs. If the topcoat layer is used, the optional finishing coat
layer can be applied over at least a portion of the topcoat layer
for further control of the drug-release rate and for improving the
biocompatibility of the coating. Without the topcoat layer, the
finishing coat layer can be deposited directly on the reservoir
layer.
[0102] Sterilization of a coated medical device generally involves
a process for inactivation of micropathogens. Such processes are
well known in the art. A few examples are e-beam, ETO
sterilization, and irradiation. Most, if not all, of these
processes can involve an elevated temperature. For example, ETO
sterilization of a coated stent generally involves heating above
50.degree. C. at humidity levels reaching up to 100 mole % for
periods of a few hours up to 24 hours. A typical EtO cycle would
have the temperature in the enclosed chamber to reach as high as
above 50.degree. C. within the first 3-4 hours then and fluctuate
between 40.degree. C. to 50.degree. C. for 17-18 hours while the
humidity would reach the peak at 100 mole % and maintain above 80
mole % during the fluctuation time of the cycle.
[0103] The process of the release of a drug from a coating having
both topcoat and finishing coat layers includes at least three
steps. First, the drug is absorbed by the polymer of the topcoat
layer at the drug-polymer layer/topcoat layer interface. Next, the
drug diffuses through the topcoat layer using the void volume
between the macromolecules of the topcoat layer polymer as pathways
for migration. Next, the drug arrives at the topcoat
layer/finishing layer interface. Finally, the drug diffuses through
the finishing coat layer in a similar fashion, arrives at the outer
surface of the finishing coat layer, and desorbs from the outer
surface. At this point, the drug is released into the blood vessel
or surrounding tissue. Consequently, a combination of the topcoat
and finishing coat layers, if used, can serve as a rate-limiting
barrier. The drug can be released by virtue of the degradation,
dissolution, and/or erosion of the layer(s) forming the coating, or
via migration of the drug through the amorphous polymeric layer(s)
into a blood vessel or tissue.
[0104] In one embodiment, any or all of the layers of the stent
coating can be made of an amorphous terpolymer described herein,
optionally having the properties of being biologically
degradable/erodable/absorbable/resorbable, non-degradable/biostable
polymer, or a combination thereof. In another embodiment, the
outermost layer of the coating can be limited to an amorphous
terpolymer as defined above.
[0105] To illustrate in more detail, in a stent coating having all
four layers described above (i.e., the primer, the reservoir layer,
the topcoat layer and the finishing coat layer), the outermost
layer is the finishing coat layer, which can be made of an
amorphous terpolymer described herein and optionally having the
properties of being biodegradable or, biostable, or being mixed
with an amorphous terpolymer. The remaining layers (i.e., the
primer, the reservoir layer and the topcoat layer) optionally
having the properties of being biodegradable or, biostable, or
being mixed with an amorphous terpolymer. The polymer(s) in a
particular layer may be the same as or different than those in any
of the other layers, as long as the layer on the outside of another
bioabsorbable should preferally also be bioabsorbable and degrade
at a similar or faster relative to the inner layer. As another
illustration, the coating can include a single matrix layer
comprising a polymer described herein and a drug.
[0106] If a finishing coat layer is not used, the topcoat layer can
be the outermost layer and should be made of an amorphous
terpolymer described herein and optionally having the properties of
being biodegradable or, biostable, or being mixed with an amorphous
terpolymer. In this case, the remaining layers (i.e., the primer
and the reservoir layer) optionally can also be fabricated of an
amorphous terpolymer described herein and optionally having the
properties of being biodegradable or, biostable, or being mixed
with an amorphous terpolymer The polymer(s) in a particular layer
may be the same as or different than those in any of the other
layers, as long as the outside of another bioabsorbable should
preferably also be bioabsorbable and degrade at a similar or faster
relative to the inner layer.
[0107] If neither a finishing coat layer nor a topcoat layer is
used, the stent coating could have only two layers--the primer and
the reservoir. In such a case, the reservoir is the outermost layer
of the stent coating and should be made of an amorphous terpolymer
described herein and optionally having the properties of being
biodegradable or, biostable, or being mixed with an amorphous
terpolymer. The primer optionally can also be fabricated of an
amorphous terpolymer described herein and optionally one or more
biodegradable polymer(s), biostable polymer(s), or a combination
thereof. The two layers may be made from the same or different
polymers, as long as the layer on the outside of another
bioabsorbable should preferably also be bioabsorbable and degrade
at a similar or faster relative to the inner layer.
[0108] Any layer of a coating can contain any amount of an
amorphous terpolymer described herein and optionally having the
properties of being biodegradable or, biostable, or being mixed
with an amorphous terpolymer. Non-limiting examples of
bioabsorbable polymers and biocompatible polymers include
poly(N-vinyl pyrrolidone); polydioxanone; polyorthoesters;
polyanhydrides; poly(glycolic acid); poly(glycolic
acid-co-trimethylene carbonate); polyphosphoesters;
polyphosphoester urethanes; poly(amino acids); poly(trimethylene
carbonate); poly(iminocarbonates); co-poly(ether-esters);
polyalkylene oxalates; polyphosphazenes; biomolecules, e.g.,
fibrin, fibrinogen, cellulose, cellophane, starch, collagen,
hyaluronic acid, and derivatives thereof (e.g., cellulose acetate,
cellulose butyrate, cellulose acetate butyrate, cellulose nitrate,
cellulose propionate, cellulose ethers, and carboxymethyl
cellulose), polyurethane,; polyesters, polycarbonates,
polyurethanes, poly(L-lactic acid-co-caprolactone) (PLLA-CL),
poly(D-lactic acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(D-lactic acid-glycolic acid
(PDLA-GA), poly(L-lactic acid-glycolic acid (PLLA-GA),
poly(DL-lactic acid-glycolic acid (PDLLA-GA), poly(D-lactic
acid-co-glycolide-co-caprolactone) (PDLA-GA-CL), poly(L-lactic
acid-co-glycolide-co-caprolactone) (PLLA-GA-CL), poly(DL-lactic
acid-co-glycolide-co-caprolactone) (PDLLA-GA-CL), poly(L-lactic
acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(glycolide-co-caprolactone)
(PGA-CL), or any copolymers thereof.
[0109] Any layer of a stent coating can also contain any amount of
a non-degradable polymer, or a blend of more than one such polymer
as long as it is not mixed with a bioabsorbable polymer or any
layer underneath the non-degradable layer comprise a bioabsorbable
polymer. Non-limiting examples of non-degradable polymers include
poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl
methacrylate), poly(2-ethylhexyl methacrylate), poly(lauryl
methacrylate), poly(2-hydroxylethyl methacrylate), poly(ethylene
glycol (PEG) acrylate), poly(PEG methacrylate), methacrylate
polymers containing 2-methacryloyloxyethylphosphorylcholine (MPC),
PC1036, and poly(n-vinyl pyrrolidone, poly(methacrylic acid),
poly(acrylic acid), poly(hydroxypropyl methacrylate),
poly(hydroxypropyl methacrylamide), methacrylate polymers
containing 3-trimethylsilylpropyl methacrylate, and copolymers
thereof.
[0110] A coating formed of the terpolymer described herein can
degrade within about 1 month, 2 months, 3 months, 4 months, 6
months, 12 months, 18 months, or 24 months after implantation of a
medical device comprising the coating. In some embodiments, the
coating can completely degrade or fully absorb within 24 months
after implantation of a medical device comprising the coating.
Method of Fabricating Implantable Device
[0111] Other embodiments of the invention, optionally in
combination with one or more other embodiments described herein,
are drawn to a method of fabricating an implantable device. In one
embodiment, the method comprises forming the implantable device of
a material containing an amorphous terpolymer described herein,
optionally with one or more other biodegradable or biostable
polymer or copolymers.
[0112] Under the method, a portion of the implantable device or the
whole device itself can be formed of the material containing a
biodegradable or biostable polymer or copolymer. The method can
deposit a coating having a range of thickness over an implantable
device. In certain embodiments, the method deposits over at least a
portion of the implantable device a coating that has a thickness
of.ltoreq.about 30 micron, or.ltoreq.about 20 micron,
or.ltoreq.about 10 micron, or.ltoreq.about 5 micron,
or.ltoreq.about 3 micron.
[0113] In certain embodiments, the method is used to fabricate an
implantable device selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the method is used
to fabricate a stent.
[0114] In some embodiments, to form an implantable device formed
from a polymer, a polymer or copolymer optionally including at
least one bioactive agent described herein can be formed into a
polymer construct, such as a tube or sheet that can be rolled or
bonded to form a construct such as a tube. An implantable device
can then be fabricated from the construct. For example, a stent can
be fabricated from a tube by laser machining a pattern into the
tube. In another embodiment, a polymer construct can be formed from
the polymeric material of the invention using an injection-molding
apparatus.
[0115] Non-limiting examples of polymers, which may or may not be
the amorphous terpolymers defined above, that can be used to
fabricate an implantable device include poly(N-acetylglucosamine)
(Chitin), Chitosan, poly(hydroxyvalerate), poly(lactide-co-
glycolide), poly(hydroxybutyrate),
poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,
poly(L-lactic acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(D-lactic acid-glycolic acid
(PDLA-GA), poly(L-lactic acid-glycolic acid (PLLA-GA),
poly(DL-lactic acid-glycolic acid (PDLLA-GA), poly(D-lactic
acid-co-glycolide-co-caprolactone) (PDLA-GA-CL), poly(L-lactic
acid-co-glycolide-co-caprolactone) (PLLA-GA-CL), poly(DL-lactic
acid-co-glycolide-co-caprolactone) (PDLLA-GA-CL), poly(L-lactic
acid-co-caprolactone) (PLLA-CL), poly(D-lactic
acid-co-caprolactone) (PDLA-CL), poly(DL-lactic
acid-co-caprolactone) (PDLLA-CL), poly(glycolide-co-caprolactone)
(PGA-CL), poly(thioesters), poly(trimethylene carbonate),
polyethylene amide, polyethylene acrylate, poly(glycolic
acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g.,
PEO/PLA), polyphosphazenes, biomolecules (e.g., fibrin, fibrinogen,
cellulose, starch, collagen and hyaluronic acid), polyurethanes,
silicones, polyesters, polyolefins, polyisobutylene and
ethylene-alphaolefin copolymers, acrylic polymers and copolymers
other than polyacrylates, vinyl halide polymers and copolymers
(e.g., polyvinyl chloride), polyvinyl ethers (e.g., polyvinyl
methyl ether), polyvinylidene halides (e.g., polyvinylidene
chloride), polyacrylonitrile, polyvinyl ketones, polyvinyl
aromatics (e.g., polystyrene), polyvinyl esters (e.g., polyvinyl
acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides
(e.g., Nylon 66 and polycaprolactam), polycarbonates,
polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon,
rayon-triacetate, cellulose and derivates thereof (e.g., cellulose
acetate, cellulose butyrate, cellulose acetate butyrate,
cellophane, cellulose nitrate, cellulose propionate, cellulose
ethers, and carboxymethyl cellulose), and copolymers thereof.
[0116] Additional representative examples of polymers that may be
suited for fabricating an implantable device include ethylene vinyl
alcohol copolymer (commonly known by the generic name EVOH or by
the trade name EVAL), poly(butyl methacrylate), poly(vinylidene
fluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available from
Solvay Solexis PVDF of Thorofare, N.J.), polyvinylidene fluoride
(otherwise known as KYNAR, available from ATOFINA Chemicals of
Philadelphia, Pa.),
poly(tetrafluoroethylene-co-hexafluoropropylene-co-vinylidene
fluoride), ethylene-vinyl acetate copolymers, and polyethylene
glycol.
Method of Treating or Preventing Disorders
[0117] An implantable device according to the present invention can
be used to treat, prevent or diagnose various conditions or
disorders. Examples of such conditions or disorders include, but
are not limited to, atherosclerosis, thrombosis, restenosis,
hemorrhage, vascular dissection, vascular perforation, vascular
aneurysm, vulnerable plaque, chronic total occlusion, patent
foramen ovale, claudication, anastomotic proliferation of vein and
artificial grafts, arteriovenous anastamoses, bile duct
obstruction, urethral obstruction and tumor obstruction. A portion
of the implantable device or the whole device itself can be formed
of the material, as described herein. For example, the material can
be a coating disposed over at least a portion of the device.
[0118] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the inventive method
treats, prevents or diagnoses a condition or disorder selected from
atherosclerosis, thrombosis, restenosis, hemorrhage, vascular
dissection, vascular perforation, vascular aneurysm, vulnerable
plaque, chronic total occlusion, patent foramen ovale,
claudication, anastomotic proliferation of vein and artificial
grafts, arteriovenous anastamoses, bile duct obstruction, urethral
obstruction and tumor obstruction. In a particular embodiment, the
condition or disorder is atherosclerosis, thrombosis, restenosis or
vulnerable plaque.
[0119] In one embodiment of the method, optionally in combination
with one or more other embodiments described herein, the
implantable device is formed of a material or includes a coating
containing at least one biologically active agent selected from
paclitaxel, docetaxel, estradiol, nitric oxide donors, super oxide
dismutases, super oxide dismutase mimics,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl(4-amino-TEMPO),
tacrolimus, dexamethasone, dexamethasone acetate, rapamycin,
rapamycin derivatives, 40-O-(2-hydroxy)ethyl-rapamycin
(everolimus), 40-O-(2-ethoxy)ethyl-rapamycin (biolimus),
40-O-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin,
40-O-tetrazole-rapamycin, 40-epi-(N1-tetrazolyl)-rapamycin
(zotarolimus), Biolimus A9 (Biosensors International, Singapore),
AP23572 (Ariad Pharmaceuticals), pimecrolimus, imatinib mesylate,
midostaurin, clobetasol, progenitor cell-capturing antibodies,
prohealing drugs, fenofibrate, prodrugs thereof, co-drugs thereof,
and a combination thereof.
[0120] In certain embodiments, optionally in combination with one
or more other embodiments described herein, the implantable device
used in the method is selected from stents, grafts, stent-grafts,
catheters, leads and electrodes, clips, shunts, closure devices,
valves, and particles. In a specific embodiment, the implantable
device is a stent.
Examples
Example 1
Synthesis of Aliphatic Polyester Terpolymers for Stent Coating and
Drug Elution: Effect of Polymer Composition and Drug Solubility
Summary
[0121] Random terpolyesters with estimated weight-average molecular
weight (M.sub.w) ranging from 22,000 to 130,000 g/mol were prepared
by ring-opening terpolymerization of L-lactide (LA),
.epsilon.-caprolactone (CL), and glycolide (GA) in the presence of
tin (II) 2-ethylhexanoate (Sn(oct).sub.2) and 1,6-hexanediol at
170.degree. C. Coatings of these terpolyesters on bare metal stents
showed good adhesion to the stent, especially those with LA:CL:GA
composition of 3:1:1. The semi-synthetic macrolide
immunosuppressant, Everolimus, was incorporated into the
terpolyester coating, and its release from the stent was evaluated.
Unlike PLLA homopolymers, which cannot control release of most
drugs since they are immiscible and phase separate, these
terpolymers gave excellent control in a screening study, by tuning
terpolymer molecular weight, relative monomer ratio, and
drug-to-polymer ratio. Adjusting the polymer properties to improve
drug miscibility in the polymer coating was found beneficial to the
release profile.
Materials and Methods
Materials
[0122] L-lactide (LA, 98%), .epsilon.-caprolactone (CL, 99 mole %),
tin(II) 2-ethylhexanoate (Sn(oct).sub.2, 95%) and 1,6-hexanediol
(97%) were purchased from Aldrich. Glycolide (GA, 99.9 mole %) was
purchased from Polysciences, Inc. L-lactide and glycolide were
recrystallized from dry ethyl acetate, then dried under vacuum at
room temperature. For glycolide, the recrystallization was
performed twice. .epsilon.-Caprolactone and 1,6-hexanediol were
distilled over calcium hydride, and stored under nitrogen.
L-lactide, glycolide and 1,6-hexanediol were lyophilized before
use.
Characterization
[0123] .sup.1H and .sup.13C NMR spectra were recorded on a Bruker
Avance400 spectrometer. Polymer molecular weights and
polydispersity indices (M.sub.w/M.sub.n) were estimated by gel
permeation chromatography (GPC) equipped with a KNAUER HPLC Pump
K-501, three PLgel 5 .mu.m MIXED-D 300.times.7.5 mm columns, and an
RI detector K-2301. Polystyrene standards were used for
calibration. THF was used as the eluent at a flow rate of 1 mL/min.
Differential scanning calorimetry (DSC) measurements were performed
on a DuPont Instruments DSC 2910 at a scan rate of 10.degree.
C./min under a flow of nitrogen (50 mL/min).
Representative Synthesis of
poly(L-lactide-co-.epsilon.-caprolactone-co-glycolide)
[0124] L-lactide (4.88 g, 33.8 mmol), .epsilon.-caprolactone (1.0
mL, 9.0 mmol), and glycolide (0.26 g, 2.3 mmol) were introduced
into a flame-dried Schlenk tube under a stream of nitrogen. Tin(II)
2-ethylhexanoate and 1,6-hexanediol were added, and the Schlenk
tube was placed in an oil bath at 70.degree. C. under vacuum for 15
min and purged by a short release under nitrogen. This action was
repeated three times, after which the Schlenk tube was closed under
vacuum. The oil bath temperature was then increased to 170.degree.
C., and the mixture was stirred until high conversion was reached
(as noted by solidification of the reaction mixture). Following
cooling to room temperature, the mixture was dissolved in
chloroform and precipitated twice into methanol. The polymer was
isolated by filtration, then dried under vacuum at room temperature
overnight. The composition of the final polymer (relative ratio of
incorporated monomers) was determined by .sup.1H NMR spectroscopy
in CDCl.sub.3. A typical yield of purified polymer was in the range
of 60-70 mole %.
Coating and Release Studies
[0125] The polymer and polymer/drug solutions were typically
prepared from dilute solution (.about.1 weight %) of polymer or
polymer/drug in 9:1 acetone:methyl isobutyl ketone (MIBK). Two
coatings were then applied to the stents, first a polymer primer
coating, then a polymer/drug coating. In the primer coating, a
polymer solution was applied to form a coating of approximately 1
micron thickness. For the drug coating layer, a polymer/drug
solution was first prepared, by addition of everolimus to the fully
dissolved polymer, to give drug:polymer weight ratios of 1:1, 1:2,
and 1:3. The stents used in this study were Abbott MULTILINK
VISION.RTM. 12 mm stents, with OD 3.0 mm, and total surface area
0.56 cm.sup.2. The coating was carried out using an Abbott in-house
spray coater. A set drug dose of 100 .mu.g/cm.sup.2 was applied in
the drug layer. The stents were then crimped onto Vision.TM.
catheters. The coated stents were baked at 50.degree. C. for 2
hours, then subjected to electron-beam sterilization at 25 kGy. The
stent on the catheter was delivered through a simulated use model
to mimic the tortuosity of the coronary vessel, followed by
expansion by immersion into water at 37.degree. C. The coating
integrity was examined by scanning electron microscopy (SEM).
[0126] Drug release studies were performed on a type 7 USP
apparatus, using porcine serum as elution media at 37.degree. C.
Sodium azide was added to the media to prevent microbial growth.
USP apparatus 7 consists of a set of solution containers immersed
in a water bath at a constant temperature, sample holders, and a
drive assembly reciprocating the system vertically. At least 3
stents for each of the terpolymers were analyzed for drug release
on day 1 and day 3. Due to rapid everolimus degradation in the
elution media, the amount of drug released at each time point was
calculated based on the difference between the theoretical value
(estimated from the coating weight for each individual stent just
after stent coating) and that remaining on the stent. Residual drug
on each stent was extracted in 5-10 mL of acetonitrile/0.02% BHT
solution and sonicated for 30 minutes, and the resulting solutions
were analyzed by High Pressure Liquid Chromatography (Waters HPLC)
to quantify the amount of drug left on the stent. The HPLC system
consisted of a pump, column heater, temperature-controlled
autosampler, and Photodiode Array Detector (PDA) or UV detector. A
4.6.times.150 mm YMC C18 column was used, with 3 .mu.m particle
size. The mobile phase was 4:1 acetonitrile:ammonium acetate buffer
(0.02M), column temperature 50.degree. C., and autosampler
temperature 5.degree. C. The flow rate was 1.0 mL/minute, and the
detection wavelength 277 nm. Quantification of drug left on the
stent at each time point gave the percent of initial everolimus
released from each stent.
Results and Discussion
Terpolymer Synthesis
[0127] Bulk copolymerizations of LA, CL, and GA were performed at
170.degree. C. in the presence of Sn(oct).sub.2. Performing the
copolymerizations at this temperature leads to a greater degree of
randomness in the polymer structure relative to lower temperature
polymerizations. Incomplete incorporation of .epsilon.-caprolactone
into the polymer chains is observed when copolymerizing glycolide
and .epsilon.-caprolactone at temperatures below 150.degree. C.,
due to the lower reactivity of .epsilon.-caprolactone, as noted by
Lee, et al. (Lee S-H, Kim B-S, Kim S H, Choi S W, Jeong S I, Kwon I
K, Kang S W, Nikolovski J, Mooney D J, Han Y-K, Kim Y H. Elastic
biodegradable poly(glycolide-co-caprolactone) scaffold for tissue
engineering. J Biomed Mater Res 2003;66A:29-37). The need for high
molecular weight polyesters stems from their intended dual function
as stent coatings and also as barriers to control diffusion of the
drugs as small molecule additives. The random distribution of
.epsilon.-caprolactone and glycolide comonomers along the
polylactide backbone is desired from the standpoint of reducing the
otherwise high crystallinity and brittleness of polylactide, or
copolymers in which polylactide dominates physical properties.
[0128] LA:CL:GA terpolymers were prepared in the presence of trace
amounts of Sn(II) catalyst, and the aliphatic diol initiator
1,6-hexanediol (some polymerizations were performed in the absence
of added initiator). The reaction mixture was first heated at
70.degree. C. under vacuum for one hour, after which the
temperature was increased to 170.degree. C. to perform the
polymerization. By a reaction time of ten hours, the polymerization
mixture solidified. The solid polymers obtained were dissolved in
chloroform, precipitated into MeOH, and dried at room temperature
under vacuum for several hours to give the desired polymer,
typically as a white or off-white solid. As shown in Table 1, the
LA:CL:GA polymerizations were run with feed ratios of 60:25:15,
65:20:15 and 75:20:5. Gel permeation chromatography of the
terpolymer samples, eluting in THF at 1 mL/min and estimating
molecular weight against polystyrene standards, provided number-
and weight-average molecular weights, and polydispersity indices
(PDIs), of the samples.
[0129] In the .sup.1H NMR spectra of the terpolymers,
characteristic baseline separated resonances for each monomer type
were noted, and the integration values of these resonances gave the
relative ratio of monomers in each polymer sample. As expected, the
presence of different monomer sequences in the terpolymers results
in the presence of multiple resonances in the spectra. The
methylene protons of the glycolide units (H.sub.h) appeared as a
multiplet centered at 4.7 ppm, while those from the
.epsilon.-caprolactone units adjacent to the ester appear at 4.1
(H.sub.g) and 2.4 (H.sub.c) ppm. The methine protons of the lactide
units (H.sub.b) appear at 5.15 ppm. Integration of these resonances
gives monomer composition in the terpolymer, which is seen to agree
reasonably well with the monomer feed ratio, as indicated in Table
5.
[0130] Monomer sequence in these terpolymer structures is evaluated
by .sup.13C NMR spectroscopy (FIG. 3). For example, the carbonyl
region is sensitive to polymer microstructure. Carbonyl resonances
for glycolide, L-lactide, and .epsilon.-caprolactone in the
corresponding homopolymers are seen at 166, 169 and 173 ppm (see,
e.g., Srisa-ard M, Molloy R, Molloy N, Siripitayananon J, Sriyai M.
Synthesis and characterization of a random terpolymer of L-lactide,
.epsilon.-caprolactone and glycolide. Polym Int 2001;50:891-896).
As observed in the .sup.13C NMR spectrum of FIG. 1, the presence of
multiple additional resonances, arising from mixed triad sequences,
indicates that .epsilon.-caprolactone and glycolide are distributed
along the terpolymer chains rather that forming distinct blocks for
this (and the other) terpolymers prepared for this study.
Furthermore, the characteristic peak for the CL-CL-CL triad at
173.5 ppm was not observed. Given the higher percentage of lactide
monomer used, the intense carbonyl resonance at .about.169 ppm was
expected.
[0131] Thermal properties of these LA:CL:GA terpolymers were
determined by differential scanning calorimetry (DSC). Glass
transition temperature (T.sub.g) values, shown for example in FIG.
4 for terpolymer 5, were compared to estimated T.sub.g values based
on monomer composition using the Fox equation:
w LA T g , LA + w CL T g , CL + w GA T g , GA = 1 T g , LA - CL -
GA ##EQU00001##
where w.sub.LA, w.sub.CL and w.sub.GA are the weight fractions of
L-lactide, s-caprolactone and glycolide respectively (T.sub.g,LA
(332 K, 58.degree. C.), T.sub.g,CL (213 K, -60.degree. C.) and
T.sub.g,GA (308 K, 35.degree. C.) represent the corresponding
homopolymers). The experimental T.sub.g values are seen to agree
closely with those estimated by the Fox equation. For terpolyester
5 of Table 5, T.sub.g values of 39 and 37.degree. C. were measured
in the first and second heating runs, respectively, compared to a
Fox-estimated value of 34.degree. C. With few exceptions, melting
peaks were observed at higher temperatures (between 75 and
125.degree. C.) in the first heating run, suggesting a
semi-crystalline morphology of these terpolyesters, but as expected
the terpolymer melting peaks were observed at lower temperatures
than the melting temperature of pure poly(L-lactide).
Coating Integrity and Drug Release Studies
[0132] Polymer coatings on metal stents control interactions
between the underlying structural material and the surrounding
vessel tissue. Well-designed polymer coatings can reduce the
propensity for thrombosis and inflammatory reactions associated
with implantation, while concomitantly functioning to first hold,
then release, drugs into the surrounding tissue and bloodstream.
The use of biodegradable polymers, such as aliphatic polyesters,
carries the additional potential advantage of their elimination (by
degradation) allowing faster healing of the implanted region.
Drachman, et al. reported the use of
.epsilon.-caprolactone-co-lactide copolymers as coatings for
stainless steel stents, in which the stent polymer was loaded with
paclitaxel (Drachman D E, Edelman E R, Seifert P, Groothuis A R,
Bornstein D A, Kamath K R, Palasis M, Yang D, Nott S H, Rogers C.
Noeintimal thickening after stent delivery of paclitaxel: change in
composition and arrest of growth over six month. J Am Coll Cardiol
2000;36:2325-2332). The kinetic profile of the drug release showed
minimal early bursting, and reached 91% release after 56 days. Six
month after stenting, where it is assumed that polymer degradation
and drug release are complete, no significant thickening of the
neointimal area was observed with the paclitaxel-eluting
copolymer-coated stents. However no details on the characteristics
of the polymers were provided, such as the polymer molecular weight
and the relative ratios of monomers used.
[0133] The terpolymers prepared for this study were investigated
for their performance following spray coating onto the stent
substrate. The stent coating integrity was evaluated by simulated
use tests, and characterized by scanning electron microscopy (SEM)
after the test. Table 6 summarizes qualitatively the coating
integrity of the five samples, and FIGS. 5a and 5b provides two SEM
images of coated stents. The SEM image of FIG. 5a, representing a
stent coated with terpolymer 2 (LA:CL:GA=60:17:23), shows a smooth
coating with little-to-no cracking or delamination either in the
high strain areas or the non-linear link area. For terpolymers with
higher glycolide content, smooth coatings were generally observed.
However, in coatings from terpolymers having a higher
lactide-to-glycolide ratio, and/or low overall molecular weight,
cracks were often seen in the high strain area (FIG. 5b). This is
probably related to the higher T.sub.g and more brittle nature of
L-lactide-rich aliphatic polyesters relatives to CL and
GA-containing polyester structures.
[0134] Drug release profiles of the terpolymer-coated stents were
investigated by incorporating the immunosuppressant drug everolimus
into the top layer of the coating. The study was performed for a
period of 3 days to identify the presence or absence of initial
burst. We first considered a terpolyester with a composition of
68:18:14 and a weight-average molecular weight of 61,000 g/mol
(Table 5, entry 3). The drug release profile proved highly
sensitive to drug-to-polymer ratio, as seen in FIG. 6 for d/p
ratios 1/1, 1/2, and 1/3. Testing drug release of a formulation
containing d/p of 1/1 revealed a drug burst that released nearly
all drug on the first day. Such a burst is suggestive of a phase
separated system, in which the polymer matrix is ineffective at
containing the small molecule guest. Similar experiments using a
d/p of 1/2 revealed a significantly slower release, likely the
result of less substantial phase separation, though possibly still
above percolation. In experiments using a d/p of 1/3, no burst is
seen; instead a very slow initial release is followed by a complete
shut-down of the release system. These data suggested that lower
d/p ratios are preferred, and that a finer tuning of polymer
characteristics can be used to improve the release profiles.
[0135] We then considered the influence of polymer molecular weight
and composition on the drug release profile. For terpolymers 1 and
4, with similar molecular weights (M.sub.n .about.13,000 g/mole)
but different compositions, drug release was much faster at higher
glycolide content. For terpolymer 1, with LA:CL:GA of 61:21:18, the
drug release was significantly faster, with a cumulative drug
release of 84 % after 3 days. Compare this to terpolymer 4, with
LA:CL:GA of 77:17:6, which for the same time-frame and d/p reached
only 34% of cumulative drug release (Table 6, entry 4). This
increase in release rate is a function of higher glycolide content
in the terpolymer, which serves to increase polymer hydrophilicity,
decreases drug solubility and promotes its release. An added factor
may be that the expected crystallinity for terpolymer 4 is greater
than for terpolymer 1, further contributing to the difference in
release. Faster hydrolysis as a function of greater glycolide
content would also increase release rate, though this would be
expected over a longer time-frame than that studied here. Polyester
molecular weight is also important, as seen in terpolymers 1 and 2,
with an approximate LA:CL:GA composition of 60:20:20. Drug release
slows with higher molecular weight (Table 6, entries 1 and 2 and
FIG. 7), while for a terpolymer with a lower incorporation of
glycolide (Table 6, entries 4 and 5) the drug release profile shows
only a modest difference on day 1, but significant difference on
day 3.
TABLE-US-00005 TABLE 5
Poly(L-lactide-co-.epsilon.-caprolactone-co-glycolide) copolymers
prepared. LA:CL:GA Polymer M.sub.n M.sub.w T.sub.g.sup.a Terpolymer
Mon:init:cat feed ratio composition (g/mole) (g/mole) PDI (.degree.
C.) 1 750:1:0.2 65:20:15 61:21:18 13000 22000 1.63 26 2 750:1:0.2
60:25:15 60:17:23 25000 41000 1.67 30 3 4600:0:1 65:20:15 68:18:14
61000 101000 1.65 32 4 750:1:0.2 75:20:5 77:17:6 13000 23000 1.83
35 5 4100:1:2 76:19:5 78:18:4 50000 130000 2.61 37 .sup.aT.sub.g
value for the second heating run.
TABLE-US-00006 TABLE 6 Coating integrity and drug release with
terpolymers containing a drug-to-polymer ratio of 1-to-3..sup.a
M.sub.w Coating Drug release (%) Terpolymer.sup.b (g/mole)
integrity day 1 day 3 1.sup.c 22000 Good 58 84 2.sup.c 41000 Good
38 53 3.sup.d 101000 Good 18 33 4.sup.c 23000 sticky/cracked 22 34
5.sup.c 130000 Good 16 18 .sup.a .sup.aEverolimus release was
performed in porcine serum. .sup.bsame polymers from Table 1.
.sup.c1 wt % polymer coated from 9:1 acetone:MIBK. .sup.d2 wt %
polymer coated from 4:1 acetone:MIBK.
CONCLUSION
[0136] Terpolymers prepared from L-lactide, .epsilon.-caprolactone
and glycolide were synthesized by ring-opening polymerization in
the bulk, with tin(II) 2-ethylhexanoate at 170.degree. C. These
random terpolymers could be prepared with estimated weight-average
molecular weights as high as .about.100,000 g/mole, and at
appropriate monomer combinations the polymers were able to provide
excellent coating integrity on stents. The drug release using a
terpolymer with a composition of .about.60:20:20 (LA:CL:GA) showed
good control, especially when terpolymers with relatively high
molecular weight were used. The ratio of the comonomers in the
terpolyester tuned the relative hydropholicity/hydrophobicity of
the polymer coating, allowing the release of everolimus based on
its solubility in the matrix. Increased glycolide content in the
terpolyester enhanced the hydrophilicity of the polymer matrix
leading to an accelerated release of everolimus. The
diffusion-based release was observed from the early stage of the
release study without an initial burst. Thus, drug release
characteristics can be altered by optimizing the polymer
composition and molecular weight to retard or accelerate the
release kinetics. Taken together, the data indicate that these
polymers are attractive candidate for drug delivery applications in
which coatings are a critically important component of the
system.
[0137] While particular embodiments of the present invention have
been shown and described, it will be obvious to those skilled in
the art that changes and modifications can be made without
departing from this invention in its broader aspects. Therefore,
the claims are to encompass within their scope all such changes and
modifications as fall within the true sprit and scope of this
invention.
* * * * *